Ketogenic diet as a glycine lowering therapy in nonketotic hyperglycinemia and impact on brain glycine levels

Shelkowitz, Emily; Saneto, Russell P.; Al-Hertani, Walla; Lubout, Charlotte M. A.; Stence, Nicholas V.; Brown, Mark S.; Long, Patrick; Walleigh, Diana; Nelson, Julie A.; Perez, Francisco E.; Shaw, Dennis W. W.; Michl, Emma J.; Van Hove, Johan L. K.

doi:10.1186/s13023-022-02581-6

Orphanet Journal of Rare Diseases

Table 1 Overview of patient molecular, biochemical and clinical data

From: Ketogenic diet as a glycine lowering therapy in nonketotic hyperglycinemia and impact on brain glycine levels

Patient	1	2	3	4	5	6
Plasma glycine µmol/L (at diagnosis)	820	2108	1410	744	838	459
CSF glycine µmol/L (at diagnosis)	88	439	345	71	119	118.8
Ratio CSF:plasma glycine	0.11	0.21	0.24	0.10	0.14	0.26
Molecular diagnosis	AMT: c. c.959G > A p.(Arg320His)^a and c.515 T>C p.(Leu172Pro)	GLDC: c.1545G>C p.(Arg515Ser)^a and whole gene deletion (8.8 Mb 9p-deletion)^d	GLDC: c.1166 C>T p.(Ala389Val)^b and c. 1401 + G>A	GLDC: c.806C>T, p.(Thr269Met)^b and c.1952A>G,p.(His651Arg)	GLDC: Homozygous^c c.2311G>A,.(Gly771Arg)	AMT: c.959C>G p.(Arg320His); c.1063del, p.(Ser355Leufs*2)
Age at presentation	DOL 3	< DOL 2	DOL 3	10 weeks	2 weeks	2 months
Predicted phenotype	Attenuated-poor	Severe	Attenuated-poor	Attenuated-Intermediate	Severe	Severe
Indication for KD initiation	Refractory epilepsy	Seizures, encephalopathy and poor prognosis	Refractory epilepsy	Escalating benzoate requirement, abnormal movements, self-harming behaviors and increasing antiepileptic medications	Seizure escalation	Adjunctive therapy
Age at diet initiation	6 months	1 month	6 months	26 months	9 weeks	6 months
SB dose prior to KD (mg/kg/d)	475	550	480	390 → 600	500	400
SB dose on KD (mg/kg/d)	200	325	128	300	290	200
Clinical impact	Increased alertness, decreased spasticity	Unable to assess d/t limited length of trial	Decreased seizure frequency (~ 4/day to ~ 4/week)	Decreased seizure frequency and antiepileptic medications, decreased hyperactivity, decreased self-harming behaviors	Difficult to evaluate d/t short time on benzoate therapy only	Decreased seizure intensity
KD ratio	3:1	3:1	3:1	3.2: 1	3.25:1 to 4:1	3:1
Tolerance	Discontinued after ~ 6 months Remains on SB 450 mg/kg/d	Discontinued at ~ 1 week Remains on SB 650 mg/kg/d	Remains on diet > 11 months Well-tolerated	Remains on diet > 2 years Well-tolerated	Remains on diet > 14 months Well-tolerated	Remains on diet > 6 months Well-tolerated

Summary of the pertinent biochemical, molecular, and clinical data available at the time of patients’ diagnosis used to predict the long-term phenotypes and summary of details regarding the indication for ketogenic diet initiation, procedure for initiation, and any observed benefits and side effects
Normal plasma glycine levels in neonates are 125–450 µM, normal CSF glycine levels in neonates are 4.7–15.4 µM, and the normal CSF:plasma glycine ratio is ≤ 0.02
CSF, cerebral spinal fluid; DOL, day of life; KD, ketogenic diet; SB, sodium benzoate, expressed in mg/kg/day; d/t, due to
^aKnown variant without residual activity upon expression and associated with severe outcome
^bKnown variant with residual activity upon protein expression in COS cells and associated with attenuated outcome
^cBiallelic with exonic copy number variant excluded
^d9p-deletion syndrome on one allele as previously published⁴⁴

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ISSN: 1750-1172

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